PROJECT SUMMARY This proposal aims at using novel measures of regional cerebral arterial elasticity to clarify the role that arterial wall stiffening (arteriosclerosis) may play in age-related cognitive decline. In some older adults, cognitive decline becomes sufficiently severe to start impacting daily activities (mild cognitive impairment) and often progresses to Alzheimer's disease or other forms of dementia. Whereas dementia is considered to be irreversible, many of the risk factors contributing to it, including arteriosclerosis, are preventable, making the early detection of these conditions and of their specific roles in the pathway to cognitive decline, of paramount importance. In this proposal we focus on cognitive control functions, which are ubiquitous and crucial to everyday life, and include the setting, maintenance, and flexible adjustment of task goals representations. The overarching objective of this project is to systematically map the relationships between cerebrovascular, anatomical, functional, and behavioral variations in cognitive control over the adult life span (N=300, age range = 25-75, 60 people, 50% females per decade). We aim to determine whether profiles of regional variability in cerebrovascular function map onto individual differences in the structural and functional integrity of brain areas/networks that support cognitive control, and in the performance of cognitive control tasks. This approach is enabled by an innovative non-invasive optical imaging method, pulse-DOT (cerebral arterial pulse measured with diffuse optical tomography), which assesses the elasticity of cerebral arteries directly (instead of by inference from global, systemic measures) allowing us to map regional cerebral arterial stiffening with high signal to noise and reliability. In addition to pulse-DOT, individuals' profiles will include measures of (a) grey and white matter integrity; (b) brain function (MRI-based resting state functional connectivity [rsFC], event-related brain potentials [ERPs], and analysis of EEG oscillatory patterns); and (c) performance in behavioral paradigms investigating cognitive control. The specific aims of this proposal are to establish the relationships between individual differences in arterial elasticity in regions associated with cognitive control and: (AIM 1) volumetric/white matter integrity of these same brain regions and their connections; (AIM 2) the functional organization of cognitive control networks and task-related changes during control tasks; (AIM 3) specific behavioral evidence that cognitive control is affected. This approach will provide an unprecedented level of precision for investigating such relationships. If successful, this research will demonstrate early, pre-clinical links between arterial dysfunction and the emergence of brain and cognitive problems, and will help devise strategies for possible individualized, precision-medicine-inspired interventions to stave off early phases of age-related cognitive decline and dementia.